The possible role of the Akt signaling pathway in schizophrenia

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Available online at www.sciencedirect.com

www.elsevier.com/locate/brainres

Review

The possible role of the Akt signaling pathway in schizophrenia Wenhua Zhenga,b,n, Haitao Wanga, Zhiwen Zenga, Jun Linc, Peter J. Littled, Lalit K. Srivastavae, Remi Quirione a

Neuropharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China c Department of Anesthesiology, SUNY Downstate Medical Center, Brooklyn, NY, USA d Discipline of Pharmacy, School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC 3083, Australia e Douglas Mental Health University Institute, McGill University, Montreal, Canada b

art i cle i nfo

ab st rac t

Article history:

Serine/threonine protein kinase v-akt murine thymoma viral oncogene homolog (Akt) is one

Accepted 25 June 2012

of the survival kinases with multiple biological functions in the brain and throughout the

Available online 4 July 2012

body. Schizophrenia is one of the most devastating psychiatric disorders. Accumulating

Keywords:

evidence has indicated the involvement of the Akt signaling pathway in the pathogenesis of

Akt

this disorder. Genetic linkage and association studies have identified Akt-1 as a candidate

Dopamine receptor

susceptibility gene related for schizophrenia. The level of Akt-1 protein and its kinase activity

Neurodevelopment

decreased significantly both in white blood cells from schizophrenic patients and in

Schizophrenia

postmortem brain tissue of schizophrenic patients. Consistent with these findings, altera-

Antipsychotic

tions in the upstream and downstream pathways of Akt have also been found in many psychiatric disorders. Furthermore, both typical and atypical antipsychotic drugs modify the Akt signaling pathway in a variety of conditions relative to schizophrenia. In addition as a survival kinase, Akt participates in neurodevelopment, synaptic plasticity, protein synthesis and neurotransmission in the central nervous system. It is thought that reduced activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway could at least partially explain the cognitive impairment, synaptic morphologic abnormality, neuronal atrophy and dysfunction of neurotransmitter signaling in schizophrenia. In addition, reduced levels of Akt may increase the effects of risk factors on neurodevelopment, attenuate the effects of growth factors on neurodevelopment and reduce the response of patients to antipsychotic agents. More recently, the role of Akt signaling in the functions of schizophrenia susceptibility genes such as disrupted-in-schizophrenia 1 (DISC-1), neuregulin-1 (NRG-1) and dysbindin-1 has been reported. Thus, Akt deficiency may create a context permissive for the expression of risk-gene effects in neuronal morphology and function. This paper reviews the role of Akt in the pathophysiology of schizophrenia and as a potential therapeutic strategy targeting Akt. & 2012 Elsevier B.V. All rights reserved.

n Corresponding author at: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun-Yat-sen University, Guangzhou 510006, China. Fax: þ86 20 39943027. E-mail address: [email protected] (W. Zheng).

0006-8993/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.brainres.2012.06.032

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Contents 1. 2. 3. 4. 5.

6.

7. 8.

9.

1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 The phosphatidylinositol 3-kinase (PI3K) or Akt signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 Overview of PI3K/Akt signaling in neurodegenerative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Pathophysiology of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Role of PI3K/Akt signal cascade in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 5.1. Evidence from genetic studies and postmortem data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 5.2. Evidence from animal models of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 5.3. Effects of antipsychotic drugs on PI3K/Akt/GSK signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Mechanisms by which Akt may affect the pathogenesis of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 6.1. Role of Akt in neurodevelopment and synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 6.2. Akt dominantly suppresses neuronal atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 6.3. Akt as a downstream target and effector of dopaminergic receptor signaling. . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Inhibitory circuit alterations in schizophrenia and interplay with Akt. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Susceptibility genes for schizophrenia and their interaction with Akt. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 8.1. DISC-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 8.2. NRG-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 8.3. Dysbindin-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

Introduction

Schizophrenia is one of the most severe psychiatric disorders. There is considerable evidence that one of the possible pathophysiological mechanisms may involve an increased number of dopamine D2 receptors (D2R), receptor supersensitivity, overproduction of dopamine, or reduced degradation of dopamine in the brain (Kahn, 1980). However, the dopaminergic hyperactivity hypothesis cannot explain all the symptoms and antipsychotics that block the effects of dopamine cannot alleviate all the symptoms (Hashimoto et al., 1993). The precise molecular mechanisms underlying schizophrenia are still largely unknown. Increasing evidence shows that schizophrenia is a polygenic disorder resulting from an interaction between genes and environmental factors (Tsuang, 2000). There is also evidence that intracellular signaling pathways play an important role in the pathogenesis of schizophrenia (Coyle and Duman, 2003). The Akt signaling pathway, which is closely related to the development and function of the central nervous system, has recently attracted much attention. Evidence from postmortem brain samples of schizophrenia patients, animal models and genetic analyses have revealed disturbances in Akt signaling pathways in schizophrenia, leading to the hypothesis that Akt signaling alterations may be important in the pathogenesis of schizophrenia (Beaulieu et al., 2007). In this review, the role of the Akt signaling pathway in the development of schizophrenia and the interaction between Akt and susceptibility genes will be discussed. In addition, we will also review the effect of antipsychotic drugs on the Akt signaling pathway in neuronal tissues.

2. The phosphatidylinositol 3-kinase (PI3K) or Akt signaling pathway Akt is a serine/threonine protein kinase which was discovered in 1991 (Bellacosa et al., 1991). Akt is involved in many

cellular processes such as protein synthesis, glucose metabolism, cell proliferation, cell survival, cell migration and neural plasticity. Three Akt isoforms, Akt-1, Akt-2 and Akt-3 are encoded by the genes PKBa, PKBb and PKBg, respectively (Scheid and Woodgett, 2001). Akt-1 is involved in cellular survival, cell proliferation and protein synthesis pathway, Akt-2 is an important signaling molecule in cell proliferation (Koseoglu et al., 2007) however, the role of Akt-3 is not clear. Akt is a downstream target of PI3K in the cellular signaling of growth factor receptors such as insulin and neurotrophin receptors (Meier and Hemmings, 1999). The binding of growth factors to their cognate receptors causes conformational changes to the receptor and the activation of the receptor kinase, leading to the phosphorylation and the activation of PI3K. Once activated, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to form phosphatidylinositol (3,4,5)trisphosphate (PIP3). PIP3 then binds to the pleckstrin homology domain of Akt with high affinity and specificity leading to the membrane localization of Akt kinase (Marte and Downward, 1997). Once correctly positioned at the membrane, Akt is phosphorylated by its upstream kinases such as phosphoinositide dependent kinase 1 (PDK-1), which phosphorylates Akt at Thr308 (Sen et al., 2003) and mammalian target of rapamycin complex 2 that phosphorylates Akt at Ser473 (Sarbassov et al., 2005). The phosphorylation of Thr308 and Ser473 of Akt fully activates Akt, which then phosphorylates a diverse number of protein substrates containing the consensus sequence of RXRXXS/T (Scheid and Woodgett, 2001). These substrates include Bcl-2-associated death promoter (BAD), Caspase 9, Forkhead box protein O1 (FoxO1, FKHR), glucose transporters (GLUTs), endothelial nitric oxide synthase (eNOS), mammalian target of rapamycin (mTOR), IkB kinase (IKK), NF-KappaB, glycogen synthase kinase 3b (GSK-3b), Proline-rich Akt substrate of 40 kDa, cAMP response element-binding (CREB), p21CIP1, p27KIP1 and phosphodiesterase 3B (PDE3B) (LoPiccolo et al., 2008) and

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phosphorylation of these substrates eventually elicit multiple biological responses. A schematic presentation of how Akt plays its role by acting on different substrates is illustrated in Fig. 1. For example, Akt could activate mTOR and the activated mTOR plays its role in cell regulation by activating S6 kinase/ PKC and inhibiting p21/GSK-3b (Polak and Hall, 2009). The PI3K/ Akt/mTOR pathway is an important intracellular signaling pathway in cell proliferation, motility, apoptosis and angiogenesis (Hixon et al., 2010) and has recently been shown to participate in the pathophysiology of schizophrenia (Swiech et al., 2008). There are two isoforms, GSK-3a and GSK-3b. GSK3b is highly enriched in the brain and dysregulated GSK-3 has been implicated in several diseases including Alzheimer’s disease, bipolar disorder and even cancer (Peineau et al., 2007). Both GSK-3a and GSK-3b are constitutively active and their activity is inhibited by phosphorylation by Akt at specific residues on the kinases (Ser 21 for GSK-3a and serine 9 for GSK-3b). GSK-3b is one of the most important downstream effectors of Akt/mTOR and has been recently proposed as a contributing factor in the etiology of psychiatric disorders (Mao et al., 2009). The activity of GSK-3b decreases upon phosphorylation at serine 9 by Akt (Cross et al., 1995) and this inhibition of GSK-3 is currently believed to underlie the therapeutic usefulness of lithium for the treatment of mood disorders such as bipolar disorder (Kaladchibachi et al., 2007).

Fig. 1 – Schematic diagram showing the current understanding of Akt signaling in various biological functions. Cytokines and growth factors activate their receptors and lead to the activation of PI3K. Products of PI3K such as PIP3 recruit Akt and PDK1 to the plasma membrane leading to phosphorylation of Akt at ser308 residue by PDK1. Akt is also phosphorylated by DNA-dependent protein kinase, calcium–calmodulin kinase–kinase, ataxia telangiectasia mutated and a complex including rictor, mtor and sin1 at ser473 residue. Phosphorylation of these two residues activates Akt which in turn phosphorylates multiple proteins including GSK3, eNOS, mTor, FoxO, BAD, BAX, Casp9,MSK1, NF-kB, leading to the changes in metabolism, proliferation, survival and apoptosis.

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3. Overview of PI3K/Akt signaling in neurodegenerative disorders Besides playing an important role in the diverse diseases such as diabetes, many cancers and muscle atrophy, Akt also plays a role in the central nervous system (Schubert et al., 2004). A role for Akt signaling has been widely reported in brain development, brain ageing, neurodegenerative and psychotic disorders (Ke´ri et al., 2010). Growth factors as upstream modulators of Akt promote the survival or differentiation of developing neurons and protect neurons from atrophy and apoptosis (Connor and Dragunow, 1998). The protective effect of growth factors such as insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor (BDNF) is mediated by the activation of the PI3K/Akt pathway in many neuronal cells including hippocampal neurons and PC12 cells (Zheng and Quirion, 2004, 2006). Growth factor gene therapy has the potential to delay the progress of neurological diseases (Tuszynski, 2002). Lack of growth factor or neurotrophic factor signaling in the brain may lead to changes in Akt and downstream proteins and eventually to neuronal disorders (Dudek et al., 1997). Low expression of Akt has been related to neurodegeneration, whereas the activation of Akt protects against neuronal death (Lee et al., 2006). For example, amyloid beta peptide plays an important role in the pathology of Alzheimer’s disease (AD) and it could induce tau phosphorylation and loss of cholinergic neurons (Zheng et al., 2002), while IGF-1 protects against amyloid beta toxicity by strongly activating Akt in a PI3K-dependent manner (Wei et al., 2002). The huntingtin gene codes for a protein called the huntingtin protein and Huntington’s disease is caused by a mutation in the huntingtin gene. Mutant huntingtin induces neurodegeneration by an apoptotic mechanism in Huntington’s disease; IGF-1 activates Akt and results in a decrease in the formation of mutant huntingtin. That is Akt phosphorylates huntingtin and mediates the neuroprotective effects of IGF-1 (Humbert et al., 2002). In Parkinson’s disease, Akt signal transduction dysfunction is also linked to the loss of dopaminergic neurons (Timmons et al., 2009). Downstream targets of Akt such as GSK, FoxO, caspase 9 and mTOR are all reported to be related to neurodegenerative disorders (Zemke et al., 2007; Medina and Avila, 2010; Kim et al., 2006; Skurk et al., 2005). For example, GSK-3 activation is critical in brain aging and the cascade of detrimental events in AD, GSK-3b can induce memory deficits in vivo and inhibition of GSK-3a reduces amyloid beta peptide production (Takashima, 2006). A hallmark of neurodegenerative disorders is memory deficits (Granholm et al., 2008) and Akt has been implicated in the regulation of long-term potentiation (LTP), a cellular mechanism of learning and memory in the hippocampus (Li et al., 2010), and it is suggested that the downstream signaling of Akt, i.e., mTOR is also involved in the regulation of LTP in the hippocampus (Ghiglieri et al., 2010). Activation of the PI3K/Akt-mTOR signaling pathway participates in LTP of medial prefrontal cortex (mPFC) and long-term retention of trace fear memory (Sui et al., 2008). The survival promoting property of Akt may reduce the loss of neurons and its role in neurodevelopment and synaptic plasticity may contribute to the regulation of LTP (Kumar et al., 2005). Thus, PI3K/Akt

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signaling is considered to be neuroprotective in neurodegenerative disorders. Besides its important role in the neurodegenerative disorders, the Akt signaling pathway is widely involved in the pathogenesis of mental disorders such as schizophrenia, bipolar disorder and depression. As for schizophrenia, evidence exists for degeneration as well as brain development, although at present, evidence for the latter appears to be stronger.

4.

Pathophysiology of schizophrenia

Schizophrenia is a common mental disorder with a lifetime prevalence of 1% in the general population worldwide (van Os and Kapur, 2009). The disorder is characterized by hallucinations, delusions, disorganized speech and impairments in social cognition (Kuperberg and Heckers, 2000). Abnormalities in various neurotransmitters, early brain development and neuroplasticity may play important roles in the pathogenesis of schizophrenia (Arnold et al., 2005). Neurotransmitter systems such as dopaminergic, glutamatergic and GABAergic systems have all been implicated in the pathophysiology of schizophrenia (Lisman et al., 2008). Considerable evidence supports the hypothesis that elevated dopaminergic activity in the limbic regions of the basal ganglia may be responsible for the expression of psychotic symptoms of the disorder (Howes et al., 2009). A number of animal models of psychosis such as animals repeatedly treated with amphetamine or phencyclidine, neonatal hippocampal lesions or mutations in susceptibility genes display dopaminergic hyperactivity and/or higher expression of D2R (Seeman et al., 2005). Postmortem studies have also shown increased density of D2R in the striatum of patients with schizophrenia (Seeman et al., 1993). However, the density of D2R was reported to be unaltered in the prefrontal cortex (Urigu¨en et al., 2009). Current antipsychotic drugs are believed to alleviate the positive symptoms of schizophrenia by suppressing dopamine D2R activity (Lieberman, 2004). Another neurotransmitter related to schizophrenia is glutamate (Conn et al., 2009). The ‘‘glutamate hypothesis’’ of schizophrenia is based on the hypofunction of glutamatergic signaling via N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission (Coyle, 2006; Krystal et al., 2002). Phencyclidine (PCP), a non-competitive NMDA receptor antagonist can induce a state which shows some similarities to schizophrenia such as hallucinations, paranoia and emotional withdrawal (Javitt and Zukin, 1991). Additionally, reduction in glutamate levels or blockade of NMDA receptors leads to cognitive impairments (Krystal et al., 1994; Neill et al., 2010) that are considered to be core neuropsychological problem in schizophrenia (Kalkstein et al., 2010). The recent promising results with LY-2140023, a metabotropic glutamate receptor (mGluR) 2/3 agonist, in treating positive and negative symptoms of schizophrenia further suggest the involvement of glutamatergic mechanisms in the disease process (Patil et al., 2007; Mezler et al., 2010). Since there are interactions between dopaminergic and glutamatergic systems, it is proposed that schizophrenia may be associated with interconnected abnormalities of glutamate and dopamine transmission (Laruelle et al., 2003).

A number of studies have reported that a deficit in the g-aminobutyric acid (GABA) system, particularly that associated with parvalbumin-positive interneurons, may also be involved in schizophrenia (Lewis and Moghaddam, 2006). Postmortem studies show that the synthetic enzyme for GABA (67 kDa isoform of glutamate acid decarboxylase, GAD67) and the transporter that clears synaptic GABA (GAT1) are reduced in schizophrenia, which leads to compensatory increased expression of postsynaptic GABAA receptors in the dorsolateral prefrontal (DLPFC) and anterior cingulate cortices (Blum and Mann, 2002). The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is GABA. Furthermore, a selective agonist at extrasynaptic GABAA receptor could dose-dependently alleviate PCP-induced deficits (Damgaard et al., 2011). In addition to dopamine, glutamate and GABA, other neurotransmitters such as acetylcholine are also reported to be involved in schizophrenia. The expression of alpha7 neuronal nicotinic acetylcholine receptor (CHRNA7) is decreased in schizophrenia (Riley et al., 2000). CHRNA7 is genetically linked to an auditory gating deficit found in schizophrenics and its partial agonist (DMXB-A) is now in early clinical development for treatment of deficits in neurocognition and sensory gating in schizophrenia (Tregellas et al., 2007, 2010). Twin, family and adoption studies have provided consistent evidence that genetic factors play an important role in the etiology of schizophrenia (O’Donovan et al., 2009; Shih et al., 2004). Currently, it is hypothesized that copy number variations and polymorphisms in multiple genes as well as environmental factors, through a complex interplay, affect the development of CNS and synaptic circuits that eventually lead to the expression of the illness (Mitchell and Porteous, 2011; van Os et al., 2008; Boksa, 2008). Clinical studies and evidence from brain pathology, genetics, and neuroimaging studies are in support of the neurodevelopmental model of the origin of schizophrenia (Lewis and Levitt, 2002; Fatemi and Folsom, 2009). Genetic linkage and association studies have identified many candidate susceptibility genes related to schizophrenia such as DISC-1, NRG-1, dysbindin-1, Akt-1, MUTED and catechol-O-methyltransferase (Gogos and Gerber, 2006). Many of these genes function in the process of neuronal development, neuronal plasticity and signal transduction. Unlike neurodegenerative diseases, brain tissue of schizophrenia subjects generally does not exhibit overt features of neuronal loss and glial cell proliferation (Ross et al., 2006). However, neuroimaging studies show a range of structural brain changes, including an increased ventricular volume, reduced whole brain volume, and reductions in temporal lobe and prefrontal cortical gray matter (Levitt et al., 2010; Kempton et al., 2010). These changes are observed at the first clinical episode suggesting their possible neurodevelopmental origins (Woods et al., 2005; Vita et al., 2006). At the microscopic level, morphometric studies have shown reduced neuronal size, rather than a loss of neurons in the hippocampus, prefrontal cortex and thalamus (Selemon and Goldman-Rakic, 1999; Pennington et al., 2008). Brain tissue of subjects with schizophrenia shows some changes in neuronal morphology, e.g., reduced spine densities on the basilar dendrites of pyramidal neurons in the dorsolateral prefrontal cortex and other cortical regions (Glantz and Lewis, 2000: Broadbelt et al., 2002). The neurodevelopmental hypothesis assumes that

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schizophrenia is a neurodevelopmental disorder that affects youth in puberty and causes the neuropsychological disruption, but onset of the clinical symptoms is delayed until adult life or at least until adolescence in the great majority of cases. Why does schizophrenia begin after puberty? Weinberger speculated that the relevant developmental milestone linked to early adult life also involves the functional maturation of prefrontal temporolimbic cortical connectivity (Weinberger, 1995). Loss of cells in the thalamus may be primary or secondary to cortical or other subcortical pathology, the loss of neurons during later childhood and adolescence could lead to elimination of certain needed networks resulting in reduced synaptic proliferation, and eventually cause a reduced synapse density and disintergration of thought processes (Jones, 1997), and thus manifested symptoms occurred.

5. Role of PI3K/Akt signal cascade in schizophrenia 5.1.

Evidence from genetic studies and postmortem data

Several findings have implicated Akt in the pathophysiology of schizophrenia and Akt-1 has been identified as a potential schizophrenia susceptibility gene (Freyberg et al., 2010). Dysfunction of growth factor signaling cascades which is upstream of PI3K/Akt has also been reported in schizophrenia (Van Beveren et al., 2006). For example, mean plasma IGF-1 levels were found to be significantly lower in patients with schizophrenia (Venkatasubramanian et al., 2007) and antipsychotic treatment resulted in an elevation of serum IGF-1 levels (Venkatasubramanian et al., 2010). The functional Val66Met polymorphism of the BDNF gene is suggested to play a role in schizophrenia and mood disorders (Rybakowski, 2008). BDNF levels in schizophrenia are shown to be reduced compared to healthy subjects (Weickert et al., 2003; Ikeda et al., 2008; Jindal et al., 2010; Rizos et al., 2010), while antipsychotic drugs increase the promoter activity of the BDNF gene (Lee et al., 2010). Serum epidermal growth factor (EGF) levels are markedly reduced in schizophrenic patients (Futamura et al., 2002; Ikeda et al., 2008) and EGF receptor signaling is suggested to mediate the effects of the atypical antipsychotic clozapine (Pereira et al., 2009). A direct link between Akt/GSK-3 pathway and schizophrenia is provided by both genetic studies and postmortem data. Emamian et al. (2004) presented evidence for a decrease in Akt-1 protein levels and decreased phosphorylation of GSK-3b at Ser9 in the peripheral lymphocytes and brains of schizophrenia patients. Notwithstanding several reports to the contrary (Liu et al., 2006; Ohtsuki et al., 2004), the hypothesis that Akt-1 may be a susceptibility gene for schizophrenia is supported in several case/control samples and family cohorts (Ikeda et al., 2004, 2006; Schwab et al., 2005; Bajestan et al., 2006; Xu et al., 2007; Thiselton et al., 2008; Karege et al., 2010; Mathur et al., 2010). Tan et al. (2008) reported that an Akt-1 gene variant was associated with the risk for schizophrenia and suggested that Akt-1 variation may affect dopaminergic signaling and the expression of psychosis. An allelic variant of Akt-1 is associated with both cognitive and neuroanatomical aberrations in neural

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networks involving prefrontal cortex (Pietila¨inen et al., 2009). Postmortem brain samples from patients with schizophrenia showed significant reductions in phosphorylated Akt levels in hilar neurons of the dentate gyrus (Balu et al., 2012). Among three members of the Akt family, Akt-1 has been reported to be associated with schizophrenia and a reduced expression of total Akt-1 RNA and Akt-1 protein is observed in schizophrenia brain, while Akt-2 only shows a nonsignificant reduction (Thiselton et al., 2008). Upstream and downstream effectors of Akt may also play a role in schizophrenia. PI3K is the main upstream activator of Akt, which is involved in multiple cellular processes such as cell growth, cell differentiation, cell migration, axonal sprouting, cytoskeletal remodeling, intracellular trafficking and learning and memory. Aberrant PI3K signaling has been suggested by many studies to be a contributing factor in the pathology of schizophrenia (Waite and Eickholt, 2010). The most common downstream targets of Akt are GSK-3b, b-Catenin and CREB, which have all been implicated in the pathophysiology of the disease based on protein, mRNA and enzyme activity changes (Lang et al., 2007). For example, Souza et al. (2008) reported that GSK-3b polymorphisms might be involved in schizophrenia risk even though it may not be a significant factor in clozapine response. Park et al. (2009) reported that the GSK-3b C/C genotype is one of the main genotypes associated with schizophrenia. Benedetti et al. (2010) reported that GSK-3b may affect neuropathology of major behavioral disorders such as schizophrenia, and thus may be applied as a possible target for treatment. Although Akt affects multiple aspects in the brain, some alternation of Akt signaling may be cell-type and brain region specific. For example, NRG1 SNP is associated with decreased cerebral activation in specific brain areas related to schizophrenia, which include prefrontal, anterior cingulate, lateral and medial temporal cortex (Kircher et al., 2009), and decreased neuregulin1 signals caused schizophrenia through reducing the activity of PI3K/Akt pathway. Compared to control patients, schizophrenic patients showed significant decreases in Akt content and activity (pSer473-Akt) as well as its downstream GSK-3 levels in the dorsolateral prefrontal cortex (Zhao et al., 2006). More importantly, compared with other mental disorders such as patients with bipolar illness or unipolar depression, GSK-3 beta protein levels and GSK-3 activity are reduced by over 40% in postmortem prefrontal cortex of schizophrenic patients (Kozlovsky et al., 2000, 2001). Emamian et al. (2004) have proved that the decreased phosphorylation of GSK-3 in postmortem brain samples of schizophrenic patients, apparently resulted from reduced levels of PI3K/Akt. These data indicate that compared with other mental illness, Akt signal pathway mostly altered in the prefrontal cortex, which is the most specific region for schizophrenia.

5.2.

Evidence from animal models of schizophrenia

The increased dopaminergic activity in mice as a result of genetic deletion of dopamine transporter, or of the administration of amphetamine, methamphetamine or direct dopamine receptor agonists leads to a reduction of Akt308 phosphorylation and a concomitant activation of both GSK-3a and GSK-3b

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in the striatum (Beaulieu et al., 2004). This conclusion was supported by another transgenic mice experiment in which mice overexpressing the dopamine transporter showed 40% reduction of the extracellular dopamine concentration in the striatum and 300% increase of the basal levels of phospho-Akt (Ghisi et al., 2009). Similarly, in vivo and in vitro PCP administrations reduce the phosphorylation of Akt Ser473 and GSK-3b Ser9, resulting in decreased Akt activity and increased GSK-3b activity (Lei et al., 2008). A neurodevelopmental model of schizophrenia in the rat, the neonatal ventral hippocampus lesion (NVHL) model also shows reduced levels of phosphorylation of Akt and GSK-3 (Bychkov et al., 2007). Furthermore, in maternal infection based models, adult offsprings born to the immune activator PolyI:C-treated mothers show delay-dependent impairments in spatial working memory and recognition memory. These characteristics occur together with a marked reduction in Akt-1-positive cells in the prefrontal cortex (Bitanihirwe et al., 2010) and decreased phosphorylation of Akt in the hippocampus (Makinodan et al., 2008).

5.3. Effects of antipsychotic drugs on PI3K/Akt/GSK signaling Two major classes of antipsychotic drugs are currently recognized. The first, called typical antipsychotics are specific D2R antagonists, with haloperidol as a representative of this group. The second class, known as atypical antipsychotics (including drugs such as clozapine, olanzapine and risperidone), act on wider targets (such as 5-HT, ACh and NE) besides the D2R. Compared to the typical antipsychotics, the atypical antipsychotics provide better control of the negative and affective symptoms of schizophrenia (Stahl, 2004; Kapur and Remington, 2001). Most of the antipsychotic drugs increase the phosphorylation of Akt, while Akt-1-knockout mice are insensitive to antipsychotic drugs (Chen and Lai, 2010). Clozapine activates both Akt- and GSK-3b phosphorylation and increases total cellular and intranuclear levels of b-catenin. The phosphorylation of Akt is mediated by the PI3K signaling pathway, while the phosphorylation of GSK-3b is mediated by Wnt signal pathways (Kang et al., 2004). Chronic administration of clozapine or subchronic administration of valproate causes an elevation of GSK-3b protein levels in frontal cortex (Kozlovsky et al., 2006). Both typical and atypical antipsychotics induce Ser21/9 phosphorylation of GSK-3a/b. Haloperidol increases the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increased phosphorylation of Akt for more than 1 h (Roh et al., 2007). Similarly, in clinical studies, haloperidol treatment may compensate for the decreased levels of endogenous Akt1 in the frontal cortex of people with schizophrenia (Emamian et al., 2004). These studies show the importance of Akt/GSK-3 axis in the action of mood modifying drugs and the mechanism of antipsychotics’ action may be mediated in part by the Akt/GSK-3 system. A significant side-effect of the atypical antipsychotic drugs such as clozapine, risperidone and olanzapine is the treatment-dependent development of metabolic syndrome including impaired glucose metabolism and type 2 diabetes (Henderson et al., 2009; Yasui-Furukori et al., 2009). It is

interesting that Akt also plays an essential role in glucose metabolism by regulating glucose transporter expression and promoting glucose uptake into muscle and fat cells (Wofford et al., 2008). Thus, promoting the level of Akt may target both the schizophrenia symptoms and the side-effects of antipsychotic drugs.

6. Mechanisms by which Akt may affect the pathogenesis of schizophrenia 6.1. Role of Akt in neurodevelopment and synaptic plasticity The neurodevelopmental hypothesis of schizophrenia suggests that a disruption in brain development during early life underlies the later emergence of symptoms during adulthood (Marenco and Weinberger, 2000). Emerging evidence indicates that Akt-1 plays a pivotal role in brain development. Akt-1 is highly expressed in mammalian brain and it is involved in neuronal survival, neuronal excitability and synaptic plasticity. Akt has been reported to play a crucial role in neurite outgrowth. For example, Akt can phosphorylate GSK and GSK inactivation promotes neurite outgrowth in cultured neurons (Dill et al., 2008). Other substrates of Akt such as mTOR, CREB, IKKa´ and peripherin are also all involved in neurodevelopment. Chronic inhibition of PI3K or mTOR reduces soma and dendrite size and dendritic complexity as well as the density of dendritic filopodia and spines (Kumar et al., 2005). Akt acts on IKKa´ to promote neurite outgrowth, and peripherin which is also expressed in the central nervous system to promote nerve extension (Read and Gorman, 2009). Thus, reduced levels of Akt may lead to the impaired neurodevelopment. Besides the important role in neurodevelopment, Akt is also an important regulator of synaptic plasticity and its deficit leads to cognitive impairment, which is evident in patients with schizophrenia. Neurogenesis and the consequential facilitation of neuronal plasticity in the dentate gyrus strongly rely on the activation of PI3K/Akt (Bruel-Jungerman et al., 2009). Activated Akt is involved in the medial prefrontal cortex LTP and medial prefrontal cortex-dependent long-term trace fear memory (Sui et al., 2008). Further, activation of the PI3K/Akt pathway may contribute to the mechanisms of synaptic plasticity and memory consolidation by promoting cell survival via FoxO1 and protein synthesis via mTOR (Horwood et al., 2006). Disruption of mTOR signaling by rapamycin results in a reduction of late-phase LTP expression induced by high-frequency stimulation (Tang et al., 2002). NMDAR, BDNF, postsynaptic density protein 95 and PI3K have all been implicated in LTP and BDNF-TrkB signaling seems to be the downstream of NMDAR activation. NMDAR activation leads to rapid trafficking of postsynaptic density protein 95 from cell bodies to synapses and from LTP, an effect shown to be mediated by PI3K/Akt signaling (Yoshii and Constantine-Paton, 2007). GSK-3b is an important substrate of Akt and the activation of GSK-3b is associated with NMDAR-dependent synaptic plasticity. Increased GSK-3b-mediated inhibition of NMDA receptors makes an ideal case for its role in the induction of long-term depression and inhibition of LTP as both LTD and LTP are NMDA receptor-dependent (Li et al., 2009). As outlined, together with its

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substrates or signaling partners, Akt is involved in the regulation of neurodevelopment and synaptic plasticity.

6.2.

Akt dominantly suppresses neuronal atrophy

Postmortem human brain investigations show that subjects with schizophrenia have a significant reduction of whole brain and hippocampal volume, but the number of neurons and glial cells is not decreased. Therefore, the reduction of brain volume may be related to the reduction of neuronal size and atrophy. Akt could regulate cell size because the anti-atrophy effects of growth factors like IGF-1 are mediated by PI3K/Akt/mTOR and PI3K/Akt/GSK-3 pathways (Rommel et al., 2001). Akt has also been implicated in the regulation of neuronal and dendritic morphology as chronic inhibition of Akt reduces soma size, dendrite size and dendritic complexity (Kumar et al., 2005). In neurons, PTEN depletion leads to an increase in growth cone size and promotion of axonal elongation and these effects are associated with an increase in pAkt and p70S6, with pAkt promoting local protein synthesis (Ning et al., 2010). Based on the results that Akt suppresses cell atrophy and the fact that the level of Akt is significantly decreased in schizophrenia, it is possible that the low levels of Akt in the brain may affect protein synthesis leading to the neuronal atrophy and brain volume reductions observed in schizophrenia. Consistent with this, Szamosi et al. reported that patients with schizophrenia displayed decreased Akt but normal ERK ratio compared with controls. Decreased Akt ratio was associated with reduced hippocampal volume (Szamosi et al., 2012), which provides further evidence for the role of Akt in the pathophysiology of schizophrenia.

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of Akt, whereas clozapine has a longer effect on the phosphrylation of Akt (Roh et al., 2007). Therefore, Akt is inhibited following the stimulation of D2R, which supports the involvement of Akt in dopaminergic responses and schizophrenia, a schematic presentation of a potential role for Akt signaling in the development of schizophrenia is illustrated in Fig. 2. As discussed above, there are substantial evidences showing the role of the Akt pathway in the activation of dopamine receptors, specifically activation of D2R (Beaulieu 2012). Action of dopamine may be particularly important for the activation/ inactivation of Akt and its signaling pathway. But we should also notice that schizophrenia should be thought of as neurodevelopmental disorders and neurocognitive deficits, brain imaging examinations have shown the reductions in brain volume. So the alteration of Akt may not only be caused by activation/inactivation of D2R, and we should extend the search for the role of Akt in other broader changes in biologic contexts or signaling landscapes.

7. Inhibitory circuit alterations in schizophrenia and interplay with Akt The disease process of schizophrenia appears to involve deficient glutamate-mediated excitatory. Also, inhibitory circuit, which is mainly mediated by GABA, is altered as well, as mentioned above, in subjects of schizophrenia. GAD67 in DLPFC neurons and GAT1 are all decreased in schizophrenia, that is to say, compared with normal people, most of the schizophrenia patients may show deficiency in synthesis and reuptake of GABA. During the last decade, there has been

6.3. Akt as a downstream target and effector of dopaminergic receptor signaling Studies in preclinical models have identified Akt as a key signaling intermediary downstream of D2R and a target of most antipsychotic drugs (Arguello and Gogos, 2008). DA can exert its behavioral effects by acting on Akt/PKB and GSK-3. Increased DA transmission results in inactivation of Akt and concomitant activation of GSK-3 (Beaulieu et al., 2004), an effect induced by the binding of dopamine to its receptors (Fasano et al., 2008). Among the dopaminergic receptor subtypes, D2R are essential for the inhibition of Akt, although D3 receptors also potentially participate in this signaling by enhancing the D2R response, whereas D1 and D4 receptors have no effect on phospho-Akt levels (Beaulieu et al., 2007). The underlying mechanism for the inhibition of Akt by dopamine is not fully elucidated, but one possible mechanism involves a complex formation with b-arrestin 2. Activation of the D2R induces the formation of a signaling complex containing b-arrestin 2, PP2A and Akt. PP2A next dephosphorylates and inactivates Akt in the complex leading to the activation of GSK-3 (Beaulieu et al., 2005). b-Arrestin 2 acts as a scaffold protein between Akt kinase and regulatory phosphatase and is essential for the regulation of Akt by dopamine. As mentioned earlier, both haloperidol and clozapine induce Ser21/9 phosphorylation of GSK-3a/b and antagonize the effects of dopamine by activation of Akt. Haloperidol transiently increases the Ser473 phosphorylation

Fig. 2 – Schematic diagram of several pathways suggesting a potential role for Akt signaling in the development of schizophrenia. A schematic overview of the possible relationship of Akt kinase activity with the development of schizophrenia and related behaviors. Lower level or function of growth factors (GFs) such as IGF-1, BDNF, EGF and NRG-1, hyperactivity of the D2R, hypofunction of the NMDA receptor or GABA receptor leads to an inhibition of Akt and the activation of its downstream targets such as GSK3. These changes in Akt signaling lead to the disruptions of neurodevelopment and the abnormal brain functions, which eventually contribute to schizophrenia and related behaviors.

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substantial evidence showing that alterations of inhibitory circuits are a hallmark of the disorder, and that animal models reproducing these inhibitory circuit alterations can reproduce many of the behavioral and physiological manifestations of the disease. Individuals with schizophrenia tend to perform poorly on working memory tasks and to show reduced DLPFC activation. Inhibitory neurotransmitter GABA seems to be crucial during working memory processes: fast spiking GABA neurons in the monkey DLPFC are active during delay period of working memory tasks. As a kinase, Akt phosphorylates, both in vitro and in vivo, the type A GABA receptor, which is the principal receptor mediating fast inhibitory synaptic transmission in the mammalian brain. The b2 subunit of the type A GABA receptor is one of the known targets of Akt, Akt phosphorylates ser410 of the b2 subunit, which increases the number of GABA(A)Rs on the plasma membrane surface, thereby increasing the receptor-mediated synaptic transmission in neurons (Wang et al., 2003), activation of Akt increases the function of GABA, while inhibition of Akt is sufficient to increase neuronal excitability through GABA-dependent mechanisms, reduced Akt activity and subsequent reductions in GABAergic transmission have been viewed as a candidate mechanism for the heightened firing rates of ventral tegmental area dopamine neurons observed in socially defeated mice (Krishnan et al., 2008). In immature neurons, GABA depolarizes immature neurons through high-level expression of a Naþ–Kþ–2Cl cotransporter (a Cl importer). Recently, it has been identified that GABA-induced depolarizing signaling is a key target of the intrinsic factor DISC1 in regulating neuronal development during adult neurogenesis and early-postnatal neurogenesis. During this process, there is a synergistic interaction between DISC1 and GABA signaling in regulating Akt/mTOR signaling and dendritic growth of newborn neurons. Akt serves as a point of convergence and DISC1 gates depolarizing GABA-induced Akt/mTOR signaling to regulate dendritic growth (Kim et al., 2012). Other report showed that active Akt promotes differentiation of NPC into GABAergic but not glutamatergic neurons (Oishi et al., 2009). Taking all these data together, GABA, as a classic inhibitory neurotransmitter, appears to involve in the pathology of schizophrenia and there is a close relationship between Akt and GABA signaling, alteration in Akt signaling affects GABA-mediated inhibitory circuit implicated in the pathogenesis of schizophrenia.

8. Susceptibility genes for schizophrenia and their interaction with Akt It is interesting that many of these genes have roles in neurodevelopment, synapse formation, synaptic plasticity and interact with Akt and its signaling pathways.

8.1.

DISC-1

DISC1 is a gene with a wide array of functions. Within cells, DISC1 is required for neural progenitor proliferation during embryonic brain development and in the adult dentate gyrus (Mao et al., 2009). DISC-1 is predominantly associated with cytoskeletal elements that mediate neuronal migration and axonal outgrowth in brain development (Ozeki et al., 2003). DISC1 mutation in mice results in facilitation of the

psychostimulant effect of amphetamine and two-fold increased D2R levels (Lipina et al., 2010). Interestingly, pharmacological and genetic inactivation of GSK-3 effectively reverse the schizophrenia-relevant behavioral phenotypes observed in the DISC1-L100P mutants, which is a N-nitrosoN-ethylurea mutagenesis mouse mutation exhibiting schizophrenic-like behavior with profound deficits in prepulse inhibition (Lipina et al., 2011; Clapcote et al., 2007) Endogenous DISC1 protein is involved in the activation of the kinases, ERK and Akt. DISC1 interacts with the actin-binding protein girdin to regulate axonal development (Enomoto et al., 2009). Girdin directly binds to Akt and enhances its kinase activity in vitro (Anai et al., 2005). Knockdown of DISC1 leads to a decreased level of phosphorylation of Akt (Hashimoto et al., 2006). DISC1 could also directly interacts with GSK-3 and inhibits its activity, which reduces b-catenin phosphorylation and stabilizes b-catenin (Popkie et al., 2010). Interestingly, NRG-1, another important susceptibility gene for schizophrenia, is associated with increased expression of DISC1 in developing mouse brain and this effect is mediated by the PI3K/Akt signal pathway (Seshadri et al., 2010).

8.2.

NRG-1

NRG-1 is a trophic factor containing an epidermal growth factor (EGF)-like domain that signals by stimulating ErbB receptor tyrosine kinases. NRG-1 plays a role in neuronal migration, axon guidance, synapse formation, myelin formation and cell survival (Mei and Xiong, 2008). Akt may function downstream of NRG-1 as NRG-1 induces the phosphorylation of the ErbB receptors and Akt (Guo et al., 2010). The PI3K/PKB/Akt signaling pathway may mediate the neuroprotective effects of NRG, as inhibition of the PI3K activity prevents NRG-induced survival effect (Di Segni et al., 2006). NRG-1 has two isoforms, NRG-1 alpha and beta. NRG-1 beta potently and persistently activates Akt while NRG-1 alpha does not (Eckert et al., 2009). Studies have also shown that NRG-1 induced PI3K/Akt signal transduction is disrupted in schizophrenia. For example, NRG-1-induced Akt-1 phosphorylation is significantly diminished in patients with schizophrenia (Ke´ri et al., 2009). A significantly lower NRG-1-induced pAkt/Akt ratio is reported in monozygotic twins affected with schizophrenia relative to their unaffected monozygotic twins (Seres et al., 2010). So, it is possible that decreased NRG-1/ErbB signals may be related to schizophrenia through reducing the activity of PI3K/Akt pathway.

8.3.

Dysbindin-1

Dysbindin-1 was identified as a protein constituent of the dystrophin-associated protein complex (DPC) and many genetic studies have shown that variations in dysbindin-1 gene (DTNBP-1) are associated with schizophrenia (Straub et al., 2002). The expression of dysbindin-1 is significantly decreased in the hippocampus and prefrontal cortex in schizophrenia. Studies in mice with deletion of the dysbindin-1 gene have shown some aspects of the schizophreniarelated behavioral phenotype and impaired cognitive functions, including working memory (Bhardwaj et al., 2009; Cox et al., 2009). Emerging data suggest a role of dysbindin in

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dopaminergic and glutamatergic neurotransmissions (Ji et al., 2009; Papaleo and Weinberger, 2011; Jentsch et al., 2009). Overexpression of dysbindin-1 in cortical neurons protected the neurons against apoptosis via activation of the PI3K/Akt pathway. Conversely, knockdown of dysbindin by siRNA decreased the phosphorylation of Akt and facilitated neuronal death (Numakawa et al., 2004). These findings suggest that dysbindin-1 deficits may contribute to the pathophysiology of schizophrenia by negatively regulating the PI3K/Akt signaling cascade. In summary, many risk-genes for schizophrenia affect the activation of Akt-1 or regulate the Akt signaling pathway. It is obvious that the single genetic defect or single risk factor is not sufficient to cause psychiatry disorder. There probably has to be a combination of several different genetic variations, with or without other risk factors, to trigger a clinically measurable outcome. Akt may be one of the convergence points in the pathophysiology process triggered by the various susceptibility genes. Further studies are warranted to support this idea.

9.

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Akt and dopaminergic system, GABAergic system and glutamatergic system, then, how alterations in Akt signaling might affect specific neuronal populations and circuits should be investigated, a systemic study from cell model, animal model and brain sample or other samples from schizophrenia patients should be helpful. While Akt is a promising target for schizophrenia pharmacotherapy, it should be pointed out that Akt-1 has also been implicated in tumor development (Dey et al., 2010). Thus, it remains to be seen how the growth and survival promoting therapeutic potential of Akt is balanced with its tumorigenic potential. In this review, we have outlined the case for the involvement of the serine/threonine kinase Akt and its kinase activity in the pathogenesis of schizophrenia. Whether or not this can become a therapeutic target for the protection from this disease will depend upon further research which reveals targets which are specific for cell survival and neuronal protection and which can be different from the many other physiological and particular processes in which Akt is involved. Further research will include studies of upstream pathways and downstream targets.

Conclusion and future directions

The possibility of the serine/threonine kinase Akt and its signaling pathways being potential therapeutic targets in schizophrenia is supported by multiple lines of evidence as detailed in this report. Thus, activation of Akt-1, which is primarily the result of activation and upregulation of upstream molecules of Akt, including growth factors, receptor tyrosine kinases and oncogenes such as Ras and Src, may produce beneficial effects against schizophrenia (Cheng et al., 2005). The stimulation of Akt activity is also enhanced by inhibition of lipid phosphatases such as PTEN (Pitha-Rowe et al., 2009), a further upstream modulator and thus lipid phosphatase inhibitors could be potentially useful in the treatment of schizophrenia. At present, most of the information about Akt is derived from Akt-1; therefore, in future more work should be carried out to study the relationship between other isoforms of Akt and schizophrenia. Furthermore, we should also pay more attention to other downstream targets of Akt, like Bax and FoxOs, in addition to the GSK-3, the most studied downstream partner of Akt at present (Zheng et al., 2000). For example, Bax needs to be considered as the ratio of Bax/Bcl and is higher in the temporal cortex of patients with chronic schizophrenia (Jarskog et al., 2004). FoxO is an another major downstream target of Akt involved in stress and mood changes (Polter et al., 2009). FoxO transcription factors have also been regarded as critical factors in skeletal muscle atrophy and cardiomyocyte size (Sandri et al., 2004; Skurk et al., 2005). While it is tempting to speculate that Akt-FoxO pathway may participate in neuronal atrophy in schizophrenia, currently there is little evidence to support this intriguing possibility. The present studies from fMRI and PET have shown that functional differences in brain activity most commonly occur in the frontal lobes, temporal lobes and hippocampus, but we still need to understand whether the activation of the Akt pathway could be altered in region specific manner. Moreover, as we mentioned in this review, there are interplay between

Acknowledgments This work was supported by National Natural Science Fund of China (No. 30670652; No. 30970935; No. 30711120565), funding from Chinese State Administration of Foreign Experts Affairs and funding from Science and Technology Project of Guangdong Province (2011B050200005). The authors would also like to thank Mira Thakur for editorial assistance.

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